title: All-trans retinoic acid and a novel synthetic retinoid tamibarotene (Am80) differentially regulate CD38 expression in human leukemia HL-60 cells: possible involvement of protein kinase C-delta.
abstract: ATRA and a synthetic RAR agonist tamibarotene (Am80) induce granulocytic differentiation of human acute leukemia HL-60 cells and have been used in antineoplastic therapy. ATRA induces CD38 antigen during HL-60 cell differentiation, which interacts with CD31 antigen on the vascular EC surface and may induce disadvantages in the therapy. We here examined the mechanisms of the ATRA-mediated CD38 induction and compared the difference between ATRA- and tamibarotene-mediated induction. Tamibarotene-induced HL-60 cell adhesion to ECs was 38% lower than ATRA, and NB4 cell adhesion to ECs by tamibarotene was equivalent to ATRA, which induced CD38 gene transcription biphasically in HL-60 cells, the early-phase induction via DR-RARE containing intron 1, and the delayed-phase induction via RARE lacking the 5'-flanking region. In contrast to ATRA, tamibarotene induced only the early-phase induction, resulting in its lower CD38 induction than ATRA. A PKCδ inhibitor, rottlerin, and siRNA-mediated PKCδ knockdown suppressed the ATRA-induced CD38 promoter activity of the 5'-flanking region, whereas a RAR antagonist, LE540, or RAR knockdown did not affect it. Cycloheximide and rottlerin suppressed the delayed-phase induction of CD38 expression by ATRA but did not affect the early-phase induction. Moreover, ATRA, but not tamibarotene, induced PKCδ expression without affecting its mRNA stability. The diminished effect of tamibarotene on CD38-mediated HL-60 cell adhesion to ECs compared with ATRA is likely a result of the lack of its delayed-phase induction of CD38 expression, which may be advantageous in antineoplastic therapy.
authors.affiliation: Department of Advanced Biological Sciences for Regeneration, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Uruno
authors.forename: Naoya
authors.initials: N
authors.lastname: Noguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Matsuda
authors.forename: Koji
authors.initials: K
authors.lastname: Nata
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Youichiro
authors.initials: Y
authors.lastname: Chikamatsu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.forename: Hideo
authors.initials: H
authors.lastname: Harigae
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Ito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Sugawara
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics*; D001565:Benzoates / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D051745:Protein Kinase C-delta / Q000187:drug effects / Q000235:genetics; D012176:Retinoids / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D001565:Benzoates; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; D014212:Tretinoin; D051745:Protein Kinase C-delta; D051997:ADP-ribosyl Cyclase 1